This invention relates to novel analogs of cytosine nucleosides and, more particularly, to carbocyclic analogs of cytosine nucleosides in which the pentose moiety of the nucleosides is replaced by a cyclopentane ring.
Cytosine nucleosides and their 5'-phosphates are involved essentially in the biosynthesis of nucleic acids and in other biochemical processes. Cytidine and 2'-deoxycytidine are nucleoside moieties of ribonucleic acid and deoxyribonucleic acid respectively. Because of the essential and intimate involvement of cytosine nucleosides in vital biochemical processes, structural analogs of these compounds are potentially important as chemotherapeutic agents.
Currently, the best known example of a therapeutically useful cytosine nucleoside is 1-.beta.-D-arabinofuranosylcytosine, frequently designated by the acronym Ara-C. This compound has demonstrated antiviral and antineoplastic activity, as reviewed by Cohen, "Introduction to the Biochemistry of D-Arabinosyl Nucleosides", in Progress in Nucleic Acid Research and Molecular Biology, Vol. 5, Davidson and Cohn, Editors, Academic Press, New York, N.Y., 1966; and by Creasey, "Arabinosylcytosine", in Antineoplastic and Immunosuppressive Agents, Part II, Chapter 42, Sartorelli and Johns, Editors, Springer-Verlag, New York, N.Y., 1975.
Part of the molecule of cytosine nucleosides, including cytidine, 2'-deoxycytidine, and Ara-C, is a sugar (pentose) unit. The natural cytosine nucleosides and many of their analogs are subject to the action of enzymes (phosphorylases and hydrolases) which cleave the nucleosides to the sugar and pyrimidine moieties. Analogs of these nucleosides which are resistant to such enzyme cleavage may inhibit the action of certain enzymes that carry out biochemical reactions constituting the biosynthesis of nucleic acids, or they may inhibit the action of enzymes that interconvert the natural pyrimidine nucleotides. These inhibitory actions may exert profound effects on the metabolism of cells, which effects may be expressed as therapeutically useful activity.
Carbocyclic analogs of uracil nucleosides have previously been synthesized and described by Shealy and O'Dell, Journal of Heterocyclic Chemistry, Vol. 13, pp 1015-1020, October, 1976. No therapeutically useful activity was shown to be exhibited by such analogs.